Cervical cancer is the second most common cause of cancer-related mortality in women worldwide. Epidemiological and laboratory studies suggest a key role for human papillomavirus (HPV) in cervical carcinogenesis (Walboomers, J. M. et al. (1999) J. Pathol. 189:12-19; Zur, H. H. (2002) Nat. Rev. Cancer 2:342-350). Importantly, however, HPV infection alone is not sufficient for cervical carcinogenesis, and additional steps occur over years or decades following initial infection. Most HPV infections resolve spontaneously, but if an oncogenic (high risk) HPV infection persists, there may be progression to a high grade cervical dysplasia or cervical cancer. (Nobbenhuis, M. A. et al. (2001) Lancet 358:1782-1783). High risk HPVs include HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68, with HPV-16 and 18 accounting for up to 70% of cervical cancers worldwide.
The Papanicolaou (Pap) smear has become the most commonly used method to screen for cervical dysplasia. It has been a success and the incidence of cervical cancer has been dramatically reduced. However, cytology screening programs have limitations, especially limited sensitivity, estimated at only 51% (Nanda K. et al. (2000) Ann. Intern. Med. 132:810-819), and repeated tests are therefore necessary. In addition, a high-quality cytology screening program requires highly-trained personnel. Furthermore, although cytological screening programs have reduced the incidence of squamous cervical cancer (SCC), the incidence of cervical adenocarcinoma (AC) has continued to increase. The reason for this is unclear, but it may, in part, be due to difficulties detecting the precursor form of AC using conventional screening methods. (Bray, F. B. et al. (2005) Cancer Epidemiol. Biomarkers Prev. 14:2191-2199).
HPV DNA testing can be more sensitive than cytologic testing in detecting high-grade cervical dysplasia. However, HPV testing often has lower specificity than cytologic testing since most HPV infections are transient in nature. (Koliopoulous, G. M. et al. (2007) Gynecol. Oncol. 104:232-246). In order to improve the clinical specificity of the molecular HPV tests, a number of molecular markers associated with cervical cancer precursor lesions (i.e. Cervical Intra-epithelial Neoplasia (“CIN”) grades 1, 2 and 3) have been evaluated. (See e.g., Altieri D. C. (2003) Nat Rev. Cancer 3:46-54; Li C. et al. (2007) Mod. Pathol. 20:242-247; Andersson, S. et al. (2006) Br. J. Cancer 95:331-338; Martin, C. M. et al. (2006) Expert Rev. Mol. Diagn. 6:217-229; Branca, M. et al. (2006) Int. J. Gynecol. Pathol. 25:383-392; Harris C. P. et al. (2003) Genes Chromosomes Cancer 36:233-241). However, there remains a need for molecular markers in cervical dysplasia which indicate a high risk of progression to cancer.